As a member of the Pharmacology and Experimental Therapeutics (PET) Section I am involved in the development of new agents for childhood cancers, particularly the application of new molecularly targeted drugs. The primary objective of this project is to develop new agents for the treatment of childhood cancers with an emphasis on a more rational, targeted approach of drug development based on the current understanding of the molecular pathogenesis of human cancers. New molecularly targeted agents that are undergoing clinical development for adult cancers will be applied to childhood cancers based on the mechanism of action of the drug and the importance of the target in childhood cancers. The development of the raf kinase and receptor tyrosine kinase inhibitor sorafenib for children with refractory cancers serves as an example. In addition, the clinical development of novel cytotoxic agents for childhood cancers, such as the epothilone B analog ixabepilone (BMS-247550), an antitubulin agent, which inhibits tubulin depolymerization, will also be pursued. The pharmacokinetics and pharmacodynamics of these drugs will be studied and compared to results in adults. The development of the methotrexate (MTX) rescue agent carboxypeptidase-G2 (CPDG2) will be continued until FDA approval for this potentially life-saving treatment has been achieved.